WO2017106380A1 - Nanocapsules de protéine à revêtement zwitterionique détachable pour l'administration de protéine - Google Patents

Nanocapsules de protéine à revêtement zwitterionique détachable pour l'administration de protéine Download PDF

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Publication number
WO2017106380A1
WO2017106380A1 PCT/US2016/066713 US2016066713W WO2017106380A1 WO 2017106380 A1 WO2017106380 A1 WO 2017106380A1 US 2016066713 W US2016066713 W US 2016066713W WO 2017106380 A1 WO2017106380 A1 WO 2017106380A1
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pah
protein
pmpc
zwitterionic
nanocapsule
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PCT/US2016/066713
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English (en)
Inventor
Yunfeng Lu
Jie Li
Yang Liu
Jie Ren
Jing Wen
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The Regents Of The University Of California
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Priority to US16/063,221 priority Critical patent/US11103462B2/en
Priority to EP16876619.4A priority patent/EP3389641A4/fr
Publication of WO2017106380A1 publication Critical patent/WO2017106380A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to proteins disposed in nanocapsules and methods for making and using them.
  • chemotherapy is one of the major treatment modalities along with debulking surgery.
  • Major challenges in chemotherapy are linked to toxicity on healthy proliferating cells.
  • the life threatening side effects caused by the non-specific tissue distribution of drugs have restricted the systemic high dose strategy.
  • Tumor-targeting vectors have been developed for improved efficacy and reduced toxicity by altering the biodistribution of cancer drugs.
  • most of these vectors are often cleared out rapidly (with an undesired accumulation commonly in the liver, spleen or kidney) before they can reach the target site.
  • poly(ethylene glycol) (PEG) coating remains as the golden standard.
  • Zwitterionic polymers exhibit outstanding biocompatibility and a protein- adsorption-resistant ability due to their superhydrophilicity. Such neutral polymers have been clinically explored as anti-fouling coatings for blood-contacting devices by significantly reducing the surface energy of the coated surface.
  • protein nanocapsules that are coupled to zwitterionic molecules have great potential to escape opsonization, increasing accumulation in the tumor site by the enhanced permeability and retention (EPR) effect, and reducing undesired accumulation in the liver and spleen.
  • EPR enhanced permeability and retention
  • zwitterionic coatings can also prohibit cell-nanocapsule interaction, and thus such nanocapsules cannot be internalized by cancer cells after accumulation at a tumor site.
  • nanocarriers The targeted delivery of agents such as therapeutic nanocarriers to localized sites of diseased tissue is one of the hottest fields in nanomedicine.
  • MPS mononuclear phagocyte system
  • RES reticuloendothelial system
  • zwitterionic polymers can be coupled to polyallylamine to form protein nanocapsules with reduced surface energies so as to inhibit nanocapsule opsonization and interaction with macrophages.
  • EPR enhanced permeability and retention
  • typical zwitterionic polymer coated nanocarriers cannot be internalized by the tumor cells, a phenomenon which limits their use.
  • embodiments of the invention further provide protein nanocapsules with detachable zwitterionic polymers.
  • These zwitterionic elements can protect the nanocapsules from macrophage uptake, yet can detach once exposed to a low pH environment (as occurs at tumors and other sites of pathological cell growth), thereby allowing the nanocapsules to be internalized by cells in that environment.
  • Such embodiments of the invention allow the targeted delivery of agents such as therapeutic proteins to localized sites of diseased tissue.
  • the invention disclosed herein has a number of embodiments.
  • One embodiment is a method of forming a protein nanocapsule.
  • the protein nanocapsule is formed from reagents and under conditions that allow it to have a constellation of material properties that can change in different in vivo environments.
  • the method comprises coupling a zwitterionic polymer to a polyallylamine (PAH) to form a PAH conjugate having a zwitterionic moiety.
  • PAH polyallylamine
  • This zwitterion/PAH conjugate is then combined with a protein under conditions that allow the conjugate to self-assemble into a nanocapsule that surrounds the protein.
  • the protein nanocapsule is further crosslinked with a crosslinking agent.
  • the zwitterion moiety interacts with charged moieties on the nanocapsule and inhibits uptake of the nanocapsule by macrophages.
  • the zwitterion moiety then uncouples from the protein nanocapsule at a pH of less than 6.5, an event which then alters the zeta potential of the remaining PAH structure that encapsulates the protein. This allows the decoupled protein nanocarrier to then be internalized by mammalian cells.
  • the zwitterionic polymer is poly(2- methacryloyloxy ethyl phosphorylcholine) (PMPC), and this PMPC is coupled to polyallylamine (PAH) with an acid liable ketal linker to form a zwitterionic PAH-cfe- PMPC polymer shell.
  • PAH polyallylamine
  • the acid liable ketal linker is dithiobis(succinimidyl propionate) (DTSP).
  • Some embodiments of the invention comprise crosslinking the PAH-cfe-PMPC polymer shell with a crosslinking agent such as di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • a crosslinking agent such as di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • composition of matter comprising a cargo (such a therapeutic or diagnostic protein) encapsulated by a shell comprising a zwitterionic polymer.
  • the shell typically comprises the zwitterionic polymer reversibly coupled to a polyallylamine (PAH).
  • PAH polyallylamine
  • the zwitterionic polymer shell encapsulates the cargo agent, and remains coupled to the shell at a pH above 7.5 yet the detaches from the PAH at a pH less than 6.5.
  • the zwitterionic polymer is a poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and the PMPC is conjugated with the PAH with an acid liable ketal linker to form a zwitterionic PAH-cfe-PMPC polymer shell.
  • the PAH-cfe- PMPC polymer shell is crosslinked with a di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • DTSP di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate)
  • the cargo agent is a single protein.
  • Yet another embodiment of the invention is a method of delivering a cargo such as a therapeutic or diagnostic protein into a mammalian cell (e.g. a mammalian tumor cell growing in vivo at a site having a pH of less than 7).
  • a mammalian cell e.g. a mammalian tumor cell growing in vivo at a site having a pH of less than 7
  • such methods comprise combining a protein nanocapsule with the mammalian cell, the protein nanocapsule comprising a protein and a zwitterionic polymer shell comprising a zwitterionic polymer coupled with a polyallylamine (PAH).
  • PAH polyallylamine
  • polymer shell having the zwitterionic moieties encapsulates the protein in a manner that inhibits its opsonization by macrophages at a first environmental pH.
  • the zwitterionic moieties can be decoupled from the PAH shell at a second environmental pH.
  • the method comprises uncoupling the zwitterionic polymer from the PAH in a manner of that allows the resultant protein nanocarrier to then be internalized by a mammalian cell (e.g. a cancer cell at the site of a tumor).
  • Figure 1 is a schematic illustration of the synthesis of PAH-cfe-PMPC and subsequent synthesis of cfe-nProtein, in accordance with one or more embodiments of the invention.
  • Figure 2 illustrates the H'NMR spectrum of PMPC, in accordance with one or more embodiments of the invention.
  • Figure 3 illustrates the zeta potential distribution of cfe-nBSA before and after incubation at pH 6.5 for 2 hours, in accordance with one or more embodiments of the invention.
  • Figure 4 illustrates the size distribution of cfe-nBSA before and after incubation at pH 6.5 for 2 hours, in accordance with one or more embodiments of the invention.
  • Figure 5 illustrates an agarose gel analysis of native BSA (1), non-nBSA after incubation at pH 6.5 (2), at pH 7.4 (3), cfe-nBSA after incubation at pH 6.5 (4) and at pH 7.4 (5), in accordance with one or more embodiments of the invention.
  • Figure 6 illustrates native BSA incubated in a) pH 6.5 and b) pH 7.4 medium; cfe-nBSA incubated in c) pH 6.5 and d) pH 7.4 medium; non-nBSA incubated in e) pH 6.5 and d) pH 7.4 medium, in accordance with one or more embodiments of the invention.
  • One embodiment of the invention is a method of forming a protein nanocapsule.
  • the method comprises coupling a zwitterionic polymer to a polyallylamine (PAH) to form a PAH conjugate having a zwitterion moiety.
  • PAH polyallylamine
  • This PAH conjugate is then combined with a protein under conditions that allow the PAH conjugate to self-assemble into a nanocapsule that surrounds the protein.
  • the protein nanocapsule is further crosslinked with a crosslinking agent.
  • the protein nanocapsule is formed from reagents and under conditions that allow it to have a constellation of material properties.
  • the zwitterion moiety interacts with charged moieties on the nanocapsule and inhibits uptake of the nanocapsule by macrophages.
  • the zwitterion moiety uncouples from the protein nanocapsule at a pH of less than 6.5, an event which then alters the zeta potential of the remaining structure that encapsulates the protein.
  • the zwitterionic polymer is a poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), and this PMPC is coupled to polyallylamine (PAH) with an acid liable ketal linker to form a zwitterionic PAH- c e-PMPC polymer shell.
  • PAH polyallylamine
  • the acid liable ketal linker is dithiobis(succinimidyl propionate) (DTSP).
  • the zwitterionic polymer is synthesized by reversal additional fragmentation transfer (RAFT) polymerization using 2-methacryloyloxyethyl phosphorylcholine (MPC) as a monomer, 4-cyano-4-(phenylcarbonothioylthio) pentanoic acid as a chain transfer agent (CTA), and 4,4'- azobis(4-cyanovaleric acid) (ACVA) as an initiator.
  • the PMPC is further conjugated with 2,2- bis(aminoethoxy)propane prior to conjugation with the PAH.
  • Some embodiments of the invention further comprise crosslinking the PAH- c e-PMPC polymer shell with a crosslinking agent such as di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • a crosslinking agent such as di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • Other crosslinking agents can be used, for example a crosslinking agent comprising a peptide having an amino acid sequence that is cleaved by a protease.
  • the crosslinker is a degradable crosslinker.
  • a degradable crosslinker is cleaved under certain conditions, resulting in decomposition or removal of at least a portion of the polymer shell of the nanocapsule.
  • a degradable crosslinker may hydrolyze at certain pH (high or low), may be cleaved by specific enzymes (such as esterases or peptidases), may be photolytically cleaved upon exposure to certain wavelengths, or be cleaved at certain temperatures.
  • specific enzymes such as esterases or peptidases
  • crosslinkers which hydrolyze at reduced pH include glycerol dimethacrylate, which is stable at physiological pH (about 7.4), but hydrolyzes at lower pH (about 5.5).
  • Other examples of degradable crosslinkers include acetal crosslinkers described in US 7,056,901, which is incorporated by reference in its entirety.
  • composition of matter comprising a cargo such a therapeutic or diagnostic protein encapsulated by a zwitterionic polymer having a constellation of material properties.
  • a cargo such as therapeutic or diagnostic protein encapsulated by a zwitterionic polymer having a constellation of material properties.
  • These properties include a shell comprising a zwitterionic polymer reversibly coupled to a polyallylamine (PAH).
  • PAH polyallylamine
  • the zwitterionic polymer shell encapsulates the cargo agent, and remains coupled to the PAH shell at a pH above 7.5 yet the detaches from the PAH at a pH less than 6.5.
  • the zwitterionic polymer is a poly(2- methacryloyloxyethyl phosphorylcholine) (PMPC) and the PMPC is conjugated with the PAH with an acid liable ketal linker to form a zwitterionic PAH-cfe-PMPC polymer shell.
  • the PAH-cfe-PMPC polymer shell is crosslinked with a di-N-hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • the cargo agent is a single protein such as a growth factor (e.g. vascular endothelial growth factor) or a protein that induces apoptosis (e.g. tumor necrosis factor).
  • Yet another embodiment of the invention is a method of delivering a cargo such as a therapeutic or diagnostic protein into a mammalian cell, for example a mammalian tumor cell growing in an in vivo environment having a pH of less than 7.
  • a mammalian cell for example a mammalian tumor cell growing in an in vivo environment having a pH of less than 7.
  • methods comprise combining a protein nanocapsule with a mammalian cell, the protein nanocapsule comprising a protein and a zwitterionic polymer shell comprising a zwitterionic polymer coupled with a polyallylamine (PAH).
  • PAH polyallylamine
  • polymer shell having the Zwitterionic moieties encapsulates the protein in a manner that inhibits its opsonization by macrophages.
  • the zwitterionic moieties can be decoupled from the PAH shell (e.g. the PMPC decouples from the PAH at a pH below 6.5).
  • the method comprises uncoupling the zwitterionic polymer from the PAH in a manner of that allows the resultant protein nanocarrier to then be internalized by the mammalian cell.
  • Zwitterionic polymers useful in embodiments of the invention include for example poly 2-methacryloyloxylethyl phosphorylcholine (MPC), poly sulfobetaine methacrylate (SBMA) and poly carboxybetaine methacrylate (CBMA).
  • the zwitterionic polymer is a poly(2- methacryloyloxyethyl phosphorylcholine) (PMPC) and the PMPC is coupled with the PAH with an acid liable ketal linker such as dithiobis(succinimidyl propionate (DTSP) to form a zwitterionic PAH-cfe-PMPC polymer shell.
  • the PAH-c e-PMPC polymer shell is further crosslinked with an agent such as di-N- hydroxysuccinimide ester or dithiobis(succinimidyl propionate) (DTSP).
  • embodiments of the invention provide a poly(2- methacryloyloxyethyl phosphorylcholine) (PMPC) zwitterionic polymer synthesized by reversal addition fragmentation transfer (RAFT) polymerization and further conjugated with a polyallylamine (PAH) backbone through an acid liable ketal linker.
  • the resulting PAH-cfe-PMPC can self-assemble with proteins and be further crosslinked by di-N-hydroxysuccinimide esters to form protein nanocapsules denoted as cfe-nProtein.
  • These nanocapsules provide a suitable platform for protein therapeutics with a prolonged circulation time and the ability to be delivered into targeted cells.
  • a protein nanocapsule which comprises a protein core and a polymer shell with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) grafted polyallylamine hydrochloride (PAH) through an acid liable ketal linker (PAH-cfe-PMPC).
  • PMPC poly(2-methacryloyloxyethyl phosphorylcholine)
  • PAH polyallylamine hydrochloride
  • PAH-cfe-PMPC acid liable ketal linker
  • a method of synthesizing a protein nanocapsule is provided.
  • a PMPC zwitterionic polymer is synthesized by reversal addition fragmentation transfer (RAFT) polymerization (Step I) using 2-methacryloyloxyethyl phosphorylcholine (MPC) as a monomer, 4- cyano-4-(phenylcarbonothioylthio) pentanoic acid as a chain transfer agent (CTA), and 4,4'- azobis(4-cyanovaleric acid) (ACVA) as an initiator.
  • RAFT reversal addition fragmentation transfer
  • FIG. 3 presents the zeta potential distribution of cfe-nBSA.
  • the zeta potential of the cfe-nBSA centered at 0 mV, significantly different from the native BSA (-7 mV), indicating that the successful shielding of charges on the nanocapsules due to PMPC attachment.
  • the de-nBSA was incubated at pH 6.5, the zeta potential shift to +7 mV, demonstrating that the positive charge on the PAH backbone was exposed after the detachment of PMPC.
  • the size distribution measured by dynamic light scattering (DLS) ( Figure 4) also confirms the uniform size of de-nBSA around 14 nm at pH 7.4, significantly different from that of the native BSA (5 nm). After incubation at pH 6.5, the size deceased to 12 nm, which can be attributed to the smaller hydraulic radius after the detachment of hydrophilic PMPC with a large hydration layer.
  • Non-detachable PAH- «o «-PMPC was also synthesized.
  • the self-assembly of protein and PAH- «o «-PMPC and subsequent crosslinking by DTSP lead to the formation of protein nanocapsules denoted as «o «-nProtein.
  • nanocapsules with non-detachable PMPC that encapsulate BSA were synthesized (i.e. non-nBSA).
  • both fluorescein isothiocyanate (FITC) labeled non-nBSA (2 and 3) and cfe-nBSA (4 and 5) showed retention in the well, which is significantly different from the FITC labeled native BSA bearing negative charge moving towards the anode.
  • the non-nBSA didn't show charge change (2 and 3).
  • cfe-nBSA obviously gained positive charges, as significant movement towards cathode was shown. This further confirms the results of zeta potential analysis that PMPC shielding layer is detached from the nanocapsules. This pH sensitive property allows cfe-nProtein to provide targeted protein delivery towards the acidic microenvironment of tumor sites.
  • Example 1 Macrophage uptake of native BSA. tfe-nBS A and non-nBSA
  • Nanoparticles can easily be opsonized in the blood circulation and uptake by macrophages in the liver and spleen before they can ever reach the targeted site. Thus, escape from opsonization and macrophage uptake is the most important issue for targeted delivery of proteins.
  • macrophage escape capability was tested using a J774A.1 cell line, which is reticulum macrophage cells from ascites of BALB/cN mice. As is shown in Figure 6, FITC labeled native BSA showed similar moderate uptake by J774A.1 both under pH 6.5 and pH 7.4 after incubation with mouse serum ( Figure 6 a and b).
  • a mixed solution with monomer/CTA/initiator molar at a ratio of 20: 1:0.2 was prepared by dissolving 0.148 g MPC, 7 mg 4-cyano-4-(phenylcarbonothioylthio) pentanoic acid and 1.4 mg ACVA in a mixture of 0.2 mL dimethylformamide (DMF) and 0.4 mL methanol.
  • the solution was degassed by three freeze-pump-thaw cycles and purged with nitrogen to remove oxygen.
  • the degassed solution was set at 60 °C for 6 hours and the resulting PMPC was diluted with 1 mL methanol and precipitated and washed with tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • PMPC The activation of PMPC was done by EDC/NHS activation. Briefly, 0.1 g PMPC was dissolved in 1 mL methanol followed by adding 33 mg EDC (lOx molar excess) and 2 mg NHS. The active PMPC-NHS ester was further reacted with 5x molar excess of ketal linker, 2,2-bis(aminoethoxy)propane (13mg). The resulting ketal-PMPC was purified by precipitation in THF to remove the excess 2,2- bis(aminoethoxy)propane, EDC and NHS.
  • ketal-PMPC was reacted with 5x molar excess of dithiobis(succinimidyl propionate) (DTSP) in methanol with triethylamine as acid binding agent.
  • DTSP dithiobis(succinimidyl propionate)
  • the resulting NHS ester of ketal-PMPC was further purified by precipitation in THF.
  • Subsequent reaction with PAH resulted in PMPC conjugated PAH (PAH-de-PMPC), which is detachable under an acidic environment.
  • a non-detachable PMPC conjugated PAH PAH- «o «-PMPC was also synthesized by direct reaction between PAH and PMPC-NHS.
  • BSA was dialyzed against 10 mM pH 8.0 phosphate buffer. Subsequently, BSA was mixed with aqueous solution of PAH-cfe-PMPC at a molar ratio of 1 : 15 and self-assembled to nanocomplexes. The nanocomplexes were further crosslinked by reaction with DTSP at a BSA/DTSP ratio of 1 : 100 to form cfe-nBSA.
  • the nondetachable PAH- «o «-PMPC was also self-assembled with BSA and further crosslinked by DTSP to make non-nBSA.
  • the cfe-nBSA was incubated both at pH 7.5 and pH 6.5 phosphate buffer, respectively, for 2 hours and zeta potential and size distribution were further measured at pH 7.5 at a protein concentration of 0.5 mg/mL at 25 °C.
  • Murine macrophage J774A.1 was cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fatal bovine serum (FBS) and 1% penicillin/streptomycin. Cells (5000 cells/well, 96-well plate) were seeded the day before adding the nanocapsules. Native BSA, cfe-nBSA and «o «-nBSA were added into the cell medium with different pH at a final BSA concentration of 0.05 mg/ml. After incubation at 37 °C for 4 hours, the cells were washed three times with PBS and visualized with an Carl Zeiss Axio Observer inverted fluorescence microscope. CONCLUSION

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Abstract

L'invention concerne des nanocapsules de protéine, qui présentent des propriétés de matière qui changent dans différents environnements in vivo. Une fraction zwittérionique sur la surface de la nanocapsule peut protéger la protéine contre l'opsonisation dans un premier environnement, mais se détache de la nanocapsule de protéine dans un second environnement (par exemple, à un pH inférieur à 6,5). Dans des modes de réalisation de l'invention, le nanosupport de protéine détaché est ensuite internalisé par des cellules de mammifère (par exemple, des cellules tumorales).
PCT/US2016/066713 2015-12-18 2016-12-14 Nanocapsules de protéine à revêtement zwitterionique détachable pour l'administration de protéine WO2017106380A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022232552A1 (fr) * 2021-04-30 2022-11-03 The Trustees Of The University Of Pennsylvania Agents thérapeutiques à base de nanoparticules lipidiques (lnp) évitant la réponse immunitaire

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US11103462B2 (en) 2021-08-31
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US20180369159A1 (en) 2018-12-27

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